key: cord-1055263-k36u93uk
authors: Ide, Satoshi; Saito, Sho; Akazawa, Tsubasa; Furuya, Takahito; Masuda, Junichi; Nagashima, Maki; Asai, Yusuke; Ogawa, Tatsunori; Yamamoto, Ryohei; Ishioka, Haruhiko; Kanda, Kohei; Okuhama, Ayako; Wakimoto, Yuji; Suzuki, Tetsuya; Akiyama, Yutaro; Miyazato, Yusuke; Nakamura, Keiji; Nakamoto, Takato; Nomoto, Hidetoshi; Moriyama, Yuki; Ota, Masayuki; Morioka, Shinichiro; Matsuda, Wataru; Uemura, Tatsuki; Kobayashi, Kentaro; Sasaki, Ryo; Katagiri, Daisuke; Kutsuna, Satoshi; Hayakawa, Kayoko; Ohmagari, Norio
title: Extracorporeal membrane oxygenation may decrease the plasma concentration of remdesivir in a patient with severe coronavirus disease 2019
date: 2021-11-17
journal: IDCases
DOI: 10.1016/j.idcr.2021.e01343
sha: def87851e253e1eca7a604bb7667b28978ad8b2c
doc_id: 1055263
cord_uid: k36u93uk

Remdesivir is an antiviral drug that results in clinical improvement after five days of treatment and accelerates recovery by 31%. No studies have discussed the pharmacokinetic analysis of remdesivir in patients with severe COVID-19 requiring extracorporeal membrane oxygenation (ECMO). A 63-year-old American man who underwent mechanical ventilation and ECMO for severe COVID-19 was administered remdesivir for ten days. The loading dosage was 200 mg at 7 PM on day 12 and 100 mg daily at 0:00 PM from day 13 to 21, administered within 1 h. The pharmacokinetic analysis was performed. The serum creatinine concentration was within the normal range of 0.5–0.7 mg/dL during treatment. According to the pharmacokinetic analysis, the plasma concentrations of remdesivir and GS-441524 4 h after administration (C(4)) were 662 ng/mL and 58 ng/mL, respectively, and the concentrations 18 h after administration (C(18)) were 32 ng/mL and 44 ng/mL, respectively. Therefore, the half-life of remdesivir and GS-441524 was 3.2 and 35.1 h, respectively. Monitoring the plasma concentrations of remdesivir and GS-441524 in patients undergoing ECMO may be necessary.

Remdesivir, a nucleotide analog prodrug administered under compassionate use, resulted in clinical improvements in 68% of coronavirus disease (COVID-19) patients [1] . A phase Ⅲ trial in critically ill hospitalized COVID-19 patients also showed clinical improvements in 64.5% of patients after five days of treatment and accelerated the time to recovery by 31% [2] .

Remdesivir has a very short blood half-life of approximately 1 h. However, when hydrolyzed in the body, remdesivir becomes a circulating metabolite, GS-441524, with a half-life of approximately 27 h [3] . We report the pharmacokinetic data on remdesivir in a severe COVID-19 patient who required invasive ventilator support and extracorporeal membrane oxygenation (ECMO).

A 63-year-old American man with a medical history of obesity embarked on a cruise ship. He developed fever, nasal discharge, sore throat, and cough six days before admission.

The result of the polymerase chain reaction test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was positive, and he was transferred to our hospital. He had no history of smoking. Upon admission, his vital signs revealed a temperature of 102.3 °F and arterial oxygen saturation of 99% on 2 L of oxygen administration. Chest computed tomography revealed multiple pan-lobular consolidations just below the pleura of the bilateral lower lungs. The result of the blood tests is shown in Table 1 .

The patient was diagnosed with COVID-19 pneumonia, and lopinavir-ritonavir (LPV/r) 400 mg/100 mg twice daily was administered. On day 4 of hospitalization, the patient was intubated, and ventilator support was initiated owing to the exacerbation of respiratory failure. On day 6, he was subcutaneously injected with 180 μg interferon-alpha. Despite a high fraction of inspired oxygen and positive end-expiratory pressure, his oxygenation status worsened, and subcutaneous emphysema developed. Veno-venous ECMO with silicone-coated polypropylene membranes was implemented on day 8 via the right femoral vein for blood drainage and the right internal jugular vein for blood return. ng/mL, respectively, and the C 18 values on day 18 were 32 and 44 ng/mL, respectively.

Since COVID-19 treatment methods with antiviral drugs were not established in March 2020 [4] and the remdesivir was one of the candidate treatments for severe COVID-19, we have evaluated the pharmacokinetic data of remdesivir. Remdesivir inhibits SARS-CoV-2 in human cells in vitro [5] . The half-life of remdesivir is short, and when hydrolyzed to GS-441524, a nucleoside analog, in the plasma, its half-life is approximately 27 h [3] . A previous study reported pharmacokinetic data of remdesivir and GS-441524 within the first 24 h of administration in a patient with normal renal function. The plasma concentration of remdesivir immediately after administration (C 0 ) was 3317 ng/mL, with a sharp decrease to 171 ng/mL at 1 h (C 1 ) and below the quantification limit at 24 h (C 24 ). The concentrations of plasma GS-441524 were 113 ng/mL, 184 ng/mL, and 93 ng/mL at C 0 , C 1 , and C 24 , respectively [6] . Another study in 23 patients with normal renal function (creatinine clearance > 90 mL/min) revealed that the half-lives of remdesivir and GS-441524 on Days 7 and 14 combined were 0.92-1.09 h and 23.3-35.5 h, respectively. The peak concentrations of remdesivir and GS-441524 were 3220 and 231 ng/mL, respectively [7] . In our patients, the plasma concentrations of both remdesivir and GS-441524 were lower than those in previous studies [6, 7] . Additionally, the plasma concentration of remdesivir was not within the quantification limit, although blood samples were obtained 18 h after administration. Moreover, the half-life of remdesivir was three times longer than that reported in the manufacturer's sheet. Despite insufficient knowledge regarding the pharmacokinetics of remdesivir, we hypothesized that using ECMO might significantly affect its pharmacokinetics via these mechanisms: sequestration into and release from the circuit, increase in the volume of distribution (Vd), and decrease in the excretion rates [8] .

An association has been reported between the adsorption to ECMO and log P values, which indicates the compound's liposolubility and could lead to increased Vd. Midazolam and J o u r n a l P r e -p r o o f propofol have high adsorption, with log P values of 3.9 and 4.0, respectively [9] . The log P of remdesivir is 3.2, and it may be adsorbed to the circuit, although the log P of GS-441524 is -1.79 [10] . Lipophilic drugs and highly protein-bound drugs are significantly sequestered in the circuit [8] . The protein binding rate of remdesivir is as high as 87.9% [11] , and drugs with higher protein binding were found to have higher losses despite similar lipophilicity [12] . The 

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Informed Consent: Informed consent was obtained from the patient for publication.